This invention concerns a method for treating pathological states of anxiety, stress and aggressivity, and to a pharmaceutical or veterinary composition therefor. The active principle for the method and composition is an improved combination of a .beta.-adrenoceptor (.beta.-AA) with an anxiolytic agent, which provides an enhanced therapeutic effect without enhancing side effects.
Side effects, associated with the central nervous system (CNS), are often encountered by patients receiving one of the presently available anxiolytic agents such as diazepam and meprobamate. Sedation and impairment of motoricity are among the most serious side effects of this type. Consequently, these drugs must be used with caution by patients having activities requiring close attention or by operators of complex machinery.
I have found that by combining an anxiolytic agent with a .beta.-AA which does not penetrate or penetrates poorly the central nervous system, it is possible to provide a treatment for anxiety which is more complete than that which would be expected by the mere addition of effects and, simultaneously and unexpectedly, avoids the above noted side effects of the presently available regimens.
Combinations of .beta.-AA's and anxiolytic agents are known; for instance, Z. Rolinski and W. Kozak, Pol. J. Pharmacol. Pharm., 32, 731 (1980) reports that .beta.-AA's potentiate the antiaggressive action of benzodiazepine derivatives in the foot-shock induced fighting mice. The report makes no mention of any other effects.
C. Hallstrom et al., Brit. J. Psychiat., 139, 417 (1981) studied the therapeutic benefit of combining the .beta.-adrenoceptor antagonist propranolol with the well known anxiolytic agent diazepam in chronically anxious patients. They found that the combination was generally more effective than diazepam alone; however, they concluded that the addition of propranolol did not reduce the amount of diazepam required.
Combinations of .beta.-AA's and anxiolytic agents also have been reported in the patent literature. For example, P. Gherardi and G. Ferrari, U.S. Pat. No. 4,190,654, Feb. 26, 1980, describe a combination of moprolol and certain benzodiazapines. H. Buhlmann and D. Welzel, U.K. patent application No. 2,052,982-A, Feb. 4, 1981, describe a composition of an indole .beta.-AA, such as pindolol, and a benzodiazepine, such as cloxazolam, having enhanced anxiolytic activity. Belgian Pat. No. 860,526, May 8, 1978, discloses a combined formulation of either oxprenolol or metroprolol and a benzodiazepine derivative for treating anxiety. Belgian Pat. No. 763,000, Aug. 16, 1971 discloses combinations of a variety of .beta.-AA's, including oxprenolol and practolol, with a host of different tranquilizers including neuroleptic agents, benzodiazapine derivatives and meprobamate derivatives. U.K. Pat. No. 1,315,450, published May 2, 1973, corresponds in part to Belgian Pat. No. 763,000 and discloses a combined formulation of a more limited variety of B-AA's with only certain neuroleptic agents. Furthermore, U.K. Patent Specification No. 1,305,644, Feb. 7, 1973, describes a combination of .beta.-AA's and anxiolytic agents for the treatment of various heart diseases.
Also, D. J. LeCount and C. J. Squire, U.S. Pat. No. 3,959,486, May 25, 1976 and U.S. Pat. No. 4,059,622, Nov. 22, 1977, disclose a combination of a certain class of .beta.-AA's with a wide variety of drugs. The combination is stated to be useful for treating heart diseases and would cover combinations of cetamolol with benzodiazepine derivatives. However, the disclosure makes no mention of the combination being useful for treating anxiety, of employing lower than usual doses of the anxiolytic agent, or of providing an anxiolytic regimen free of deleterious CNS side effects.
The combination of the present invention is distinguished from the above reported combinations in that it combines a less than usual therapeutic dose of an anxiolytic agent and particular .beta.-AA's to provide an anxiolytic regimen free of deleterious CNS side effects.